title: JunD and JunB integrate prostaglandin E2 activation of breast cancer-associated proximal aromatase promoters.
abstract: Aromatase is the key enzyme in estrogen biosynthesis. Normal breast adipose tissue expresses low levels of aromatase via the distal promoter I.4. Breast adipose tissue surrounding a tumor exhibits excessive aromatase expression controlled by proximal aromatase promoters I.3/II, leading to high local levels of estrogen and breast cancer progression. Prostaglandin E(2) (PGE(2)) secreted by malignant breast epithelial cells activates breast cancer-associated aromatase promoters I.3/II, but silences promoter I.4, in cultured human breast adipose fibroblasts (BAF). The c-Jun N-terminal kinase 1 and p38α mitogen activated protein kinases are necessary for PGE(2) activation of aromatase promoters I.3/II; thus, we examined the roles of downstream targets, c-Jun, JunB, JunD, and activating transcription factor 2, in PGE(2)-mediated regulation of aromatase expression in BAF. PGE(2) induced JunB and JunD protein expression through protein kinase A and protein kinase C, respectively. JunB or JunD knockdown by small interfering RNA markedly reduced PGE(2)-induced total aromatase mRNA level and enzyme activity via promoters I.3/II. JunB knockdown also abrogated JunD expression. JunB stimulated, whereas JunD inhibited, aromatase promoter I.4 activity. Activating transcription factor 2 knockdown did not affect promoter-specific or total aromatase mRNA levels. c-Jun knockdown increased promoter I.4-specific and PGE(2)-induced promoters I.3/II-specific aromatase mRNA levels, leading to enhanced PGE(2)-induced total aromatase mRNA level and enzyme activity. JunD, c-Jun, and JunB bound to a CRE(-211/-199) essential for PGE(2) induction of aromatase promoters I.3/II. Taken together, JunD and c-Jun repress aromatase promoter I.4. JunD mediates, whereas c-Jun modulates, PGE(2) activation of aromatase promoters I.3/II via CRE(-211/-199). JunB also activates aromatase promoters I.3/II by maintaining JunD expression. Targeting JunD may abolish aromatase expression selectively in breast cancer tissue.
authors.affiliation: Division of Reproductive Biology Research, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA. dong-chen@northwestern.edu
authors.forename: Dong
authors.initials: D
authors.lastname: Chen
authors.forename: Scott
authors.initials: S
authors.lastname: Reierstad
authors.forename: Feng
authors.initials: F
authors.lastname: Fang
authors.forename: Serdar E
authors.initials: SE
authors.lastname: Bulun
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism / Q000473:pathology; D001141:Aromatase / Q000235:genetics* / Q000378:metabolism; D001483:Base Sequence; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D015232:Dinoprostone / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D040461:Gene Components; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D006801:Humans; D049410:Luciferases, Renilla / Q000096:biosynthesis / Q000235:genetics; D011485:Protein Binding; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism*; D050436:Regulatory Elements, Transcriptional; D014158:Transcription, Genetic; D015533:Transcriptional Activation
chemical_list: D016755:Proto-Oncogene Proteins c-jun; D049410:Luciferases, Renilla; D001141:Aromatase; D015232:Dinoprostone